Pancreatic cancer remains one of the most difficult malignancies to treat. The unmet need is clear, but so is the risk of drug development in a disease where progress has often been limited.
For Alan Sandler, Chief Development Officer at Revolution Medicines, the rationale for pursuing daraxonrasib began with a central biological fact: pancreatic cancer is overwhelmingly driven by RAS.
A Cancer Driven by RAS
“Pancreatic cancer is driven by RAS,” Sandler said. “Over 90% of patients will have some form of a RAS mutation, typically in the G12 component, but also potentially G13.”
That biology made RAS an important therapeutic target. In pancreatic cancer, RAS signaling helps malignant cells grow, survive, and continue proliferating.
“It’s highly driven by RAS,” Sandler said. “So you have a cancer that’s driven, addicted by RAS. It would be very logical to attempt to inhibit that in some way.”
The hope was straightforward: if RAS signaling could be effectively blocked, it could disrupt the biology sustaining the tumour and potentially help patients live longer and better.
The Long History of an “Undruggable” Target
The scientific rationale was compelling. The technical challenge was far more difficult.
RAS was discovered decades ago, but for many years it was regarded as an undruggable target. Scientists could identify its importance in cancer, yet they could not find a practical way to inhibit it with a drug.
Sandler recalled this challenge from his own time as a thoracic medical oncologist.
“RAS was something that was known in non-small cell lung cancer,” he said. “Basically, it was just known as one where patients treated with chemotherapy did worse than if they didn’t have RAS, but there was nothing we could do about it.”
The issue was structural. Traditional small-molecule approaches struggled because RAS did not appear to have an accessible pocket where a drug could bind and block its activity.
“There were no pockets, if you will,” Sandler said. “No areas where you could direct a small molecule to inhibit the downstream effects of RAS.”
A Different Way to Target RAS
The development of tri-complex inhibitors created a different strategy.
Rather than attempting to bind RAS directly, daraxonrasib first binds to cyclophilin A, a chaperone protein. That initial interaction creates a binary complex, which then binds to RAS.
Together, these components form a tri-complex that sterically interferes with RAS signaling and prevents downstream activity.
“Instead of binding to RAS directly, daraxonrasib binds to cyclophilin A,” Sandler explained. “That binary complex binds to RAS. You have the tri-complex, and that sterically inhibits RAS downstream and basically shuts off RAS.”
For Sandler, this approach reflects the work of scientists who challenged long-held assumptions about what was possible.
“Very clever scientists figured this out,” he said. “There are many, as we like to say, standing on the shoulders of giants along the way.”
Beyond KRAS
Another important feature of the approach is its potential activity across more than one RAS family member.
“This isn’t just against KRAS, but also HRAS and NRAS,” Sandler said.
That broader activity also raised an important concern. RAS signaling is not limited to cancer cells; it has major roles in normal biology. Targeting it broadly could therefore create toxicity risks.
“There were concerns about toxicity because RAS is critically important in normal development,” Sandler said.
Yet Revolution Medicines continued to test the concept.
“The folks at Revolution Medicines kind of dismissed the dogma that existed and tried again,” he said. “Again, it turned out to be a very good story.”
For pancreatic cancer, a disease so deeply dependent on RAS signaling, that willingness to revisit an old target with a new strategy may have opened a path that once appeared impossible.
“Maybe the Best Thing That Happened Is That Didn’t Work Out”: Alan Sandler on Daraxonrasib
Written by Nare Hovhannisyan, MD
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